Substituted pyridazinecarboxamides as kinase inhibitors
Pyridazine derivatives (e.g., Formula I) have unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
1. A compound of formula I:
or a salt thereof; wherein:
R 1 , is arylalkyl or heteroarylalkyl, each optionally substituted with 1-4 independent Z 1 ;
R 3 is hydrogen, hydroxy, alkoxy, or alkylamino;
R 6 is aryl, wherein R 6 is optionally substituted by 1-3 groups, independently selected from alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, —C(O)NR 7 R 8 , and Z 1 ;
R 7 and R 8 are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, or R 7 and R 8 together with nitrogen form a heterocyclyl or heteroaryl;
each Z 1 is halogen, CN, NO 2 , OR 15 , SR 15 , S(O) 2 OR 15 , NR 15 R 16 , C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 15 , C(O)NR 15 R 16 , OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , C(NR 16 )NR 15 R 16 , NR 15 C(NR 16 )NR 15 R 16 , S(O) 2 NR 15 R 16 , R 17 , C(O)R 17 , NR 15 C(O)R 17 , S(O)R 17 , S(O) 2 R 17 , R 16 , oxo, C(O)R 16 , C(O)(CH 2 )nOH, (CH 2 )nOR 15 , (CH 2 )nC(O)NR 15 R 16 , or NR 15 S(O) 2 R 17 , where n is independently 0, 1, 2, 3, 4, 5 or 6;
each R 15 is independently hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
each R 16 is independently hydrogen, alkenyl, alkynyl, C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl; and
each R 17 is independently C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl.
2. The compound of claim 1 , of formula II:
or a salt thereof, wherein:
R 6 is aryl, wherein R 6 is optionally substituted by alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, or —C(O)NR 7 R 8 ; and
R 7 and R 8 are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, or R 7 and R 8 together with nitrogen form a heterocyclyl or heteroaryl.
3. The compound of claim 1 , wherein R 6 is aryl substituted by alkyl, alkoxy, or —C(O)NR 7 R 8 .
4. The compound of claim 3 , wherein R 6 is aryl substituted by —C(O)NR 7 R 8 .
5. The compound of claim 1 , wherein R 6 is substituted by Z 1 .
6. The compound of claim 1 , wherein R 1 is arylalkyl optionally substituted with 1-4 independent Z 1 .
7. The compound of claim 1 , wherein R 3 is hydrogen.
8. The compound of claim 1 , wherein the compound is selected from the following:
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[4-(pyrrolidinylcarbonyl)phenyl]carboxamide (5);
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[4-(N-methylcarbamoyl)phenyl]carboxamide (6);
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(4-methoxyphenyl)carboxamide (15);
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(4-morpholin-4-ylphenyl)carboxamide (16);
{(6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-benzamide (17);
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[4-(2-morpholin-4-ylethoxy)phenyl]carboxamide (18);
{(6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-{4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide (25); and
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[4-(piperazinylcarbonyl)phenyl]carboxamide (26).
9. A method of treating a disease in a subject comprising administering to the subject a compound of claim 1 ;
wherein the disease is non-small cell lung cancer; anaplastic large cell lymphoma;
inflammatory myofibroblastic tumor: neuroblastoma; ovarian cancer; papillary renal carcinoma; glioma; or breast cancer.
10. The method of claim 9 , wherein the disease is mediated by the c-met, pecepteur d'origine nantais, or anaplastic lymphoma kinase or fusion proteins.
11. The method of claim 10 , wherein the fusion proteins are selected from echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase and nucleophosmin-anaplastic lymphoma kinase.
12. A method of treating a disease in a subject comprising administering to the subject a composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier;
wherein the disease is non-small cell lung cancer; anaplastic large cell lymphoma; inflammatory myofibroblastic tumor; neuroblastoma; ovarian cancer; papillary renal carcinoma; glioma; or breast cancer.